Utilizing the one-step and cell-type-specific sarcoma model, we identify Tppp3-expressing peripheral nerve cell as a cell type that gives rise to CCSs and demonstrate that cellular context-dependent epigenetic regulations, in conjunction with genetic abnormalities, play a fundamental role in the maintenance of the malignant phenotype and thus can be a therapeutic target in sarcoma cells. The gene discussed is TPPP3; the disease is sarcoma.